PROJECT 1 ABSTRACT Urinary stone disease (USD) is common and increasingly recognized as a chronic systemic disorder with skeletal and vascular morbidity. Recent population-based data suggest this morbidity starts, and may even be more pronounced, early in the lifecourse. The incidence of USD is increasing disproportionately among adolescents, making it critical to understand its impact on bone and vascular health in this population. Furthermore, studies of the bone-vascular link in USD are limited in adults and lacking in children, and the study of children confers advantages in mitigating against confounding co-morbid conditions that are highly prevalent among adults. Identifying modifiable factors that compromise bone strength and vascular health will facilitate the development of strategies to reduce fracture rates and cardiovascular events across the lifecourse. The primary objectives of this study are to: (1) evaluate the impact of USD on gains in bone density, structure and strength in adolescents and identify modifiable predictors of changes in bone strength via urine metabolic profiling and dietary assessment and (2) determine if USD is associated with subclinical vascular disease and if markers of vascular disease are associated with lower bone strength in adolescents with USD. The proposed work will leverage the resources of our multidisciplinary Pediatric Kidney Stone Center, combined with state-of-the-art bone imaging methods and vascular measures, to conduct the first prospective cohort study of bone quality and early markers of vascular disease in 125 adolescents (10-19 years old) with USD and 125 healthy controls matched on age, sex, and body mass index, followed over a 24 month interval. The new 2nd generation high-resolution peripheral quantitative computed tomography (HR-pQCT) device will be used to assess bone microarchitecture and micro-finite element analysis (FEA) estimates of bone strength (failure load) that are highly correlated with ex vivo biomechanical testing. Vascular assessment will combine markers of arterial stiffness (pulse wave velocity/analysis), subclinical atherosclerosis (carotid intima-media thickness), and endothelial function (EndoPAT), all of which have been shown to independently predict cardiovascular events in adults. We will also determine if DXA measures of areal BMD and bone mineral content at multiple sites (whole body, spine, hip and radius) reflect bone deficits captured by HR-pQCT and correlate with markers of vascular disease. This will be the first study to perform repeated bone and vascular measures prospectively in adults or children with USD. Concurrent longitudinal urine metabolic profiling by Litholink, three day 24-hour dietary recalls, and comprehensive measures of vitamin D-related mineral metabolism will allow for assessment of predictors including urine calcium, citrate, and uric acid excretion, dietary calcium, sodium and protein intake, and altered vitamin D and mineral homeostasis. The results of this study will serve specifically to inform future multicenter clinical trials of interventions to promote bone accrual and vascular health in adolescents with USD.